Synthesis and properties of 3-alkyl(aryl)-5-chloromethylisoxazoles

Article abstract of DOI:10.1023/A:1016398512557

3-Chloro-2-isothiocyanato-1-propenyl alkyl(aryl) ketones react with hydroxylamine hydrochloride to give 3-alkyl(aryl)-5-chloromethylisoxazole. Treatment of the latter with dimethylamine and ammonium thiocyanate leads to formation of previously unknown 3-alkyl(aryl)-5-dimethylamino(or isothiocyanato)-methylisoxazoles.

Full text of DOI:10.1023/A:1016398512557

Russian Journal of Organic Chemistry, Vol. 38, No. 3, 2002, pp. 415 418. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 3, 2002,
pp. 436 439.
Original Russian Text Copyright
2002 by Gadzhily, Aliev.
Synthesis and Properties
of 3-Alkyl(aryl)-5-chloromethylisoxazoles
R. A. Gadzhily and A. A. Aliev
Institute of Polymeric Materials, Academy of Sciences of Azerbaidjan,
ul. S.Vurguna 124, Sumgait, 373204 Azerbaidjan
Received January 4, 2001
Abstract 3-Chloro-2-isothiocyanato-1-propenyl alkyl(aryl) ketones react with hydroxylamine hydrochloride
to give 3-alkyl(aryl)-5-chloromethylisoxazole. Treatment of the latter with dimethylamine and ammonium
thiocyanate leads to formation of previously unknown 3-alkyl(aryl)-5-dimethylamino(or isothiocyanato)-
methylisoxazoles.
-Chlorovinyl ketones are known to react with
hydroxylamine hydrochloride to give mixtures of
isomeric 3- and 5-alkylisoxazoles [1]. An analogous
reaction with -dialkylaminovinyl ketone as carbonyl
neous attack by hydroxylamine on the carbonyl group
and C2 of the propenyl radical. Unlike alkyl 2,3-di-
chloro-1-propenyl ketones, aryl 2,3-dichloro-1-pro-
penyl ketones react with hydroxylamine to give only
component yields only 3-alkylisoxazoles [2, 3]. We one isomer, 3-aryl-5-chloromethylisoxazole. This
previously found that reactions of alkyl(aryl) 2,3-di- may be due to electron-acceptor character of the
chloro-1-propenyl ketones with hydroxylamine hydro- aryl radical which enhances electrophilicity of the
chloride in methanol lead to formation of 3-alkyl-
(aryl)-5-chloromethylisoxazoles [4]. However, further
studies showed that these products are mixtures of
isomeric 3-alkyl-5-chloromethyl- and 5-alkyl-3-
chloromethylisoxazoles which have similar boiling
points and are therefore difficult to separate. The
reaction of methyl 2,3-dichloro-1-propenyl ketone
with hydroxylamine hydrochloride was examined by
1H NMR spectroscopy. It was found that the product
is a 2:3 mixture of 5-chloromethyl-3-methyl- and
3-chloromethyl-5-methylisoxazoles. As shown in [1],
the formation of two isomers is the result of simulta-
carbonyl group.
In the present work we tried to avoid formation
of isomeric mixtures in the above processes. For this
purpose, we studied reactions of alkyl(aryl) 3-chloro-
2-isothiocyanato-1-propenyl ketones I with hydroxyl-
amine hydrochloride. The reactions of ketones I with
equimolar amounts of hydroxylamine hydrochloride
and potassium hydroxide gave 70 83% of 3-alkyl-
(aryl)-5-chloromethylisoxazoles II as the only prod-
ucts (Scheme 1). The formation of a single isomer
of II is explained by the presence of only one center
in molecule I, activated to nucleophilic attack.
Scheme 1.
I IV, R = Me (a), Et (b), Pr (c), i-Pr (d), Ph (e), 4-CH3C6H4 (f), 4-ClC6H4 (g).
1070-4280/02/3803-0415$27.00 2002 MAIK Nauka/Interperiodica

416
GADZHILY, ALIEV
Table 1. TLC data and UV, IR, and 1H NMR spectra of isoxazoles IIa IIg, IIIa, IIIb, IIId, IIIf, IVa, IVb, and IVe
Comp.
no.
UV spectrum (MeOH)
max, nm ( )
1
Rfa
IR spectrum, , cm
1H NMR spectrum, , ppm
IIa
IIb
IIc
0.67
0.66
0.64
0.57
0.68
0.54
0.50
0.60
0.57
0.50
0.51
222 (4550)
224 (4560)
223 (4170)
220 (4480)
240 (9530)
235 (9200)
250 (1170)
3148 ( C H), 1614 (C C, C N), 2.11 s (3H, CH3), 450 s (2H, CH2),
720 (C Cl) 6.09 s (1H, CH)
3144 ( C H), 1608 (C C, C N), 1.19 t and 2.55 q (5H, CH3CH2), 3.45 s
753 (C Cl)
(2H, CH2), 5.95 s (1H, CH)
3140 ( C H), 1610 (C C, C N),
754 (C Cl)
IId
IIe
3142 ( C H), 1625 (C C, C N), 1.25 d and 3.20 m [7H, CH(CH3)2],
750 (C Cl) 4.54 s (2H, CH2), 5.97 s (1H, CH)
3150 ( C H), 1605 (C C, C N), 4.56 s (2H, CH2), 6.5 s (1H, CH),
756 (C Cl)
7.35 m and 7.70 m (5H, Harom)
IIf
3157 ( C H), 1648 (C C, C N),
775 (C Cl)
IIg
IIIa
IIIb
IIId
IIIf
3156 ( C H), 1620 (C C, C N),
756 (C Cl)
3136 ( C H), 2160 (NCS), 1605 1.95 s (3H, CH3), 4.57 s (2H, CH2),
(C C, C N)
6.30 s (1H, CH)
245 (1098)
225 (4760)
224 (9630)
3145 ( C H), 2150 (NCS), 1618
(C C, C N)
3150 ( C H), 2160 (NCS), 1620 1.25 d and 3.30 m [7H, CH(CH3)2],
(C C, C N) 3.60 s (2H, CH2), 6.10 s (1H, CH)
3140 ( C H), 2160 (NCS), 1640 2.35 s (3H, CH3), 4.08 s (2H, CH2),
(C C, C N) 6.50 s (1H, CH), 7.18 m and
7.60 m (5H, Harom
)
IVa
IVb
IVe
0.63
0.61
0.54
221 (4420)
230 (4520)
250 (7500)
3130 ( C H), 1605 (C C, C N) 1.19 s (3H, CH3), 2.96 s (6H, NCH3),
3.55 s (2H, CH2N), 5.96 s (1H,
CH)
3145 ( C H), 1640 (C C, C N) 1.15 t and 2.55 q (5H, CH3CH2), 2.15 s
(6H, NCH3), 3.45 s (2H, NCH2),
5.95 s (1H, CH)
3138 ( C H), 1603 (C C, C N) 2.18 s (6H, NCH3), 3.60 s (2H, CH2),
6.20 s (1H, CH), 7.00 m and
7.35 m (5H, Harom
)
a
Eluent methanol chloroform.
Therefore, hydroxylamine reacts only at the carbonyl
carbon atom with subsequent cyclization.
The structure of products II IV was confirmed by
the IR, H NMR, and UV spectra and (in some cases)
by independent synthesis. In the IR spectra of II IV
1
The chlorine atom in chloromethylisoxazoles II is
very labile, and it can readily be replaced by various
nucleophiles. By reaction of compounds II with
2 equiv of ammonium thiocyanate we obtained
3-alkyl(aryl)-5-isothiocyanatomethylisoxazoles III in
70 89% yield. Treatment of isoxazoles II with
3 equiv of dimethylamine resulted in formation of
65 90% of 3-alkyl(aryl)-5-dimethylaminomethyl-
isoxazoles IV (Scheme 1).
we observed absorption bands typical of isoxazole ring
1
and substituents in position 5 (Table 1). The H NMR
spectra of II IV contained singlets from the 4-H
proton at 6.10 6.50 ppm, 5-CH2 protons at 4.45
4.56 ppm, dimethylamino group, and protons of the
alkyl or aryl substituent on C3 (Table 1). The data
of UV spectroscopy are consistent with the presence
of heteroaromatic isoxazole ring (Table 1). 3-Alkyl-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 3 2002

SYNTHESIS AND PROPERTIES OF 3-ALKYL(ARYL)-5-CHLOROMETHYLISOXAZOLES
417
Table 2. Yields, physical properties, and elemental analyses of compounds IIa IIg, IIIa IIIf, IVa, IVb, and IVd IVf
Found, %
Xa
Calculated, %
Xa
Comp. Yield,
bp,
(p, mm)
C
n2D0
d240
Formula
no.
%
C
H
N
C
H
N
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IVa
IVb
IVd
IVe
IVf
83
82
79
80
70
75
70
89
84
79
80
70
72
90
88
80
70
65
53 54 (1) 1.4836 1.2092 45.93 4.69 27.05 10.85 C5H6ClNO
59 60 (1) 1.4820 1.1660 49.97 5.98 24.89 9.82 C6H8ClNO
74 75 (2) 1.4808 1.1280 52.98 6.71 22.48 8.35 C7H10ClNO
71 72 (2) 1.4800 1.1260 52.35 6.99 22.75 8.48 C7H10ClNO
129 130 (2) 1.5710 1.1230 62.90 4.75 18.55 7.82 C10H8ClNO
125 126 (2) 1.5780 1.1084 63.99 4.57 17.49 6.87 C11H10ClNO 63.62 4.82 17.00 6.75
148 149 (3) 1.5740 1.1290 52.78 3.27 31.47 6.48 C10H7Cl2NO 52.63 3.07 31.14 6.15
138 139 (3) 1.5340 1.2387 46.20 3.97 20.58 19.23 C6H6N2SO
145 146 (3) 1.5330 1.2218 50.17 4.91 19.40 16.23 C7H8N2SO
151 152 (3) 1.5270 1.2040 52.33 5.71 17.91 15.47 C8H10N2SO
147 148 (3) 1.5250 1.1970 52.20 5.87 17.79 15.86 C8H10N2SO
45.63 4.56 26.99 10.65
49.48 5.50 24.40 9.62
52.66 6.27 22.25 8.78
52.66 6.27 22.25 8.78
62.62 4.13 18.34 7.24
46.75 3.89 20.78 18.18
50.00 4.76 19.04 16.67
52.75 5.49 17.58 15.38
52.75 5.49 17.58 15.38
168 170 (2) 1.5830 1.2280 60.57 3.89 14.25 12.65 C11H10N2SO 61.11 3.71 14.82 12.96
165 167 (2) 1.5860 1.2190 62.78 4.78 13.54 12.49 C12H10N2SO 62.60 4.62 13.91 12.17
79 81 (4) 1.4660 0.9785 59.75 8.69
90 92 (4) 1.4630 0.9537 62.40 9.15
92 93 (3) 1.4610 0.9145 64.45 9.50
129 130 (2) 1.5640 1.0834 71.41 6.83
135 137 (3) 1.5630 1.0892 72.42 7.55
20.47 C7H12N2O
18.40 C8H14N2O
16.80 C9H16N2O
13.78 C12H14N2O
12.98 C13H16N2O
60.00 8.57
62.33 9.09
64.28 9.52
71.28 6.93
72.22 7.40
20.00
18.18
16.66
13.96
12.96
a
IIa IIg, X = Cl; IIIa IIIf, X = S.
(aryl)-5-isothiocyanato(dimethylamino)methylisoxa-
zoles III and IV were also synthesized by reactions
of, respectively, 2,3-bis(isothiocyanato)- and 3-di-
methylamino-2-isothiocyanato-1-propenyl alkyl(aryl)
ketones with hydroxylamine hydrochloride.
25 C) a solution of 5.6 g (0.1 mol) of potassium
hydroxide in 70 ml of water and then 0.1 mol of
ketone I in 25 ml of methanol. The mixture was
heated for 5 h at 55 60 C, cooled, washed with
150 ml of a dilute aqueous solution of potassium
carbonate, and extracted with benzene. The extract
was dried over CaCl2, the solvent was distilled off,
and the residue was distilled under reduced pressure.
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80
spectrometer from samples prepared as thin films.
The 1H NMR spectra were measured on a Tesla
BS-487B instrument (80 MHz) from 5 10% solutions
in CCl4, CDCl3, or CD3OD using HMDS as internal
reference. The UV spectra were recorded on a Specord
UV-Vis spectrophotometer in methanol. The purity of
the products was checked by TLC on Silufol UV-254
plates with methanol chloroform as eluent. Initial
alkyl(aryl) 3-chloro-2-isothiocyanato-1-propenyl
ketones were synthesized by the procedure reported
in [5]. The yields, physical properties, and elemental
analyses of the products are given in Table 2.
3-Alkyl(aryl)-5-isothiocyanatomethylisoxazoles
IIIa IIIf (general procedure). To a solution of 15.2 g
(0.2 mol) of ammonium thiocyanate in 100 ml of
water we added dropwise (under vigorous stirring at
20 25 C) 0.1 mol of 3-alkyl(aryl)-5-chloromethyliso-
xazole IIa IIf dissolved in 25 ml of ethanol. The
mixture was heated for 4 h under reflux and was then
treated as described above.
3-Alkyl(aryl)-5-dimethylaminomethylisoxazoles
IVa, IVb, and IVe (general procedure). A solution
of 0.1 mol of 3-alkyl(aryl)-5-chloromethylisoxazole
II in 25 ml of benzene was added dropwise under
vigorous stirring at 20 25 C to a mixture of 60 ml
(0.3 mol) of 33% aqueous dimethylamine and 100 ml
of benzene. The mixture was heated for 5 h at 60
70 C, cooled, washed with 100 ml of a dilute aqueous
3-Alkyl(aryl)-5-chloromethylisoxazoles IIa IIg
(general procedure). To a solution of 7 g (0.1 mol)
of hydroxylamine hydrochloride in 25 ml of methanol
we added dropwise (under vigorous stirring at 20
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 3 2002

418
GADZHILY, ALIEV
solution of potassium carbonate, and treated as
described above.
REFERENCES
1. Kochetkov, N.K., Nesmeyanov, A.N., and Seme-
nov, N.A., Izv. Akad. Nauk SSSR, Otd. Khim. Nauk,
1952, no. 1, pp. 87 92.
Independent synthesis of 3-alkyl(aryl)-5-isothio-
cyanato(or dimethylamino)methylisoxazoles III
and IV (Table 1). To a solution of 7 g (0.1 mol) of
hydroxylamine hydrochloride in 25 ml of methanol
we added dropwise under vigorous stirring a solution
of 5.6 g (0.1 mol) of potassium carbonate in 70 ml
of water and then 0.1 mol of appropriate alkyl(aryl)
2,3-bis(isothiocyanato)- or 3-dimethylamino-2-isothio-
cyanato-1-propenyl ketone. The mixture was heated
for 5 h under reflux and was then treated as described
above. Samples of isoxazole derivatives obtained by
2. Kochetkov, N.K., Izv. Akad. Nauk SSSR, Otd. Khim.
Nauk, 1954, no. 1, pp. 47 55.
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1
different methods were identical in H NMR and IR
spectral parameters, boiling points, and refractive
indices.
5. Gadzhily, R.A. and Aliev, A.A., Azerb. Khim. Zh.,
1998, no. 3, pp. 108 113.
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